DESCRIPTION (adapted from the application) The healing of acute skin wounds proceeds through a series of overlapping stages involving the successive ingress of leukocytes and adjacent tissue cells into the wound site. These events are driven by the sequential activation of the participating cells, as defined by changes in their expression of a diverse range of molecules including cytokines, matrix macromolecules, matrix degrading enzymes and matrix receptors. Migration Stimulating Factor (MSF) is a truncated (70 kDa) isoform of fibronectin which has recently been cloned. It is a potent stimulator of new blood vessel formation (angiogenesis) and fibroblast migration; initial data suggest that it makes a significant contribution to the wound healing process. On the basis of these observations, we hypothesize that (i) a dysfunction in MSF expression contributes to the pathogenesis of chronic ulcers, (ii) assessment of MSF expression may be useful in the classification and prognosis of diabetic foot ulcers, and (iii) stimulation of endogenous MSF expression and/or exogenously applied MSF may promote the healing of diabetic foot ulcers. In order to test this hypothesis, we specifically propose to: a. Document the expression of MSF, other related molecules, and angiogenesis in histological sections of chronic diabetic foot ulcers and acute experimental wounds in diabetic patients and healthy controls. b. Ascertain the effects of rhMSF and IGD peptide analogues on target epithelial cells, fibroblasts and endothelial cells cultured on different macromolecular substrata and in an organotypic co-culture model of wound healing, under both normal and hyperglycemic conditions. c. Elucidate the role of the extracellular matrix and organotypic co-culture on the induction of MSF expression by TGFbeta isoforms. d. Assess the effect of rhMSF and selected IGD analogues in animal models of normal and diabetic wound healing.